Early Exposure to Anesthesia and Learning Disabilities in a Population-based Birth Cohort

Abstract

EXPOSURE to alcohol and some anesthetic and sedative drugs cause histopathologic changes in the developing brains of animals.1–3Implicated drugs include N -methyl-d-aspartate glutamate receptor antagonists (e.g. , ketamine, nitrous oxide) and agents with γ-aminobutyric acid A mimetic properties (e.g. , pentobarbital, diazepam, isoflurane, halothane, propofol). Some studies suggest that even relatively brief single exposures trigger changes, especially when combinations of agents are used.1–6In one report, histologic neurodegeneration was associated with a diminished capacity to retain learned behaviors.7It is not known whether findings in rodent models can be extrapolated to humans, but emerging histologic data in nonhuman primates8tend to confirm findings in rodents. These findings have engendered considerable concern among the U.S. Food and Drug Administration and others.5Except for case series reporting developmental outcomes of critically ill neonates and children undergoing repair of congenital heart disease,9–12which have multiple limitations, there are no data that can yield insight into whether exposure to anesthesia and surgery during human development causes clinically relevant impairment in neural development.One challenge to determining whether exposure to anesthesia and surgery in early life impairs neural development is defining relevant outcomes. Learning disabilities (LD) may be an appropriate outcome measure. Children with LD experience problems with one or more of the basic psychological processes involved in understanding or in using spoken or written language, which may manifest itself in an imperfect ability to listen, think, speak, read, write, spell, or perform mathematical calculations. Because learning disabilities are routinely sought on the basis of standardized individualized testing in educational settings and because of the relatively high incidence rate of LD,13this outcome is available in large populations of children.The purpose of the current study was to determine whether there was an association between exposure to anesthesia during the first 4 yr of life and the development of any learning disability in a birth cohort of children in Olmsted County, Minnesota.The Mayo Clinic and Olmsted Medical Center Institutional Review Boards (both in Rochester, Minnesota) approved this study. A birth cohort of children born in Rochester, Minnesota, identified in previous work by the authors13–16formed the basis of the current study. All children (n = 8,548) born between January 1, 1976, and December 31, 1982, to mothers residing at the time of delivery in the five Olmsted County, Minnesota, townships (comprising Minnesota Independent School District No. 535, the Rochester public and private school system) were identified through computerized birth certificate information obtained from the Minnesota Department of Health, Division of Vital Statistics. To ascertain vital status (still living in Rochester, moved, or deceased), for each member of the birth cohort during the 1995–1996 school year, resources available from the Rochester Epidemiology Project,17Minnesota Independent School District No. 535, the Reading Center/Dyslexia Institute of Minnesota, and the Minnesota Department of Health were used. Children who left Olmstead County before age 5 yr (i.e. , moved or died; n = 2,830) were not included in the final study cohort.14Through the Rochester Epidemiology Project, all diagnoses and surgical procedures recorded at all Rochester medical facilities are indexed for automated retrieval. This diagnostic index expedites retrieval of the unit (or dossier) medical record, which includes the history of all encounters in the hospital, community and ambulatory medical and social services, emergency department, outpatient clinics, and home visits as well as laboratory and psychological test results from birth until patients no longer reside in the community. The evaluation and instructional resources of Minnesota Independent School District No. 535, the school system for the city of Rochester, are of high quality, and the district has a long tradition of excellent care and management of children with all types of handicapping conditions, including LD. Through a contractual research agreement, all public (19 primary, 3 junior high, 3 high schools) and nonpublic (12 primary, 10 junior high, 4 high schools) schools gave permission to access their richly documented cumulative educational records for every child from this birth cohort. Under a second research agreement, permission was obtained to access the resources of the privately owned Reading Center/Dyslexia Institute of Minnesota, the only private tutoring agency in the community during the years relevant to this study. The Reading Center/Dyslexia Institute of Minnesota files included a pool of some 3,000 evaluations and outcomes of tutorial instruction that spanned nearly 50 yr. All of these records, including the results of all individuall